Abstract Efficient oncology clinical trial design requires optimal endpoint selection. Previous standard oncologic endpoints of binary dose-limiting toxicity in phase I, dichotomous tumor response in phase II, and overall survival in phase III are all being appropriately challenged as inefficient, imprecise, or impractical. These endpoints require reconsideration in the current era, where therapies are increasingly targeted, are sub- population specific, have non-cytotoxic mechanisms of action, and where, in many diseases, multiple endpoints or effective lines of treatment exist. In this project we propose 3 highly interactive yet distinct specific aims related to the development, validation, and implementation of novel endpoints in oncology clinical trials: 1) novel use of continuous metrics of adverse events (including multiple event types and cycles of treatment) alone and in concert with preliminary efficacy measures as phase I trial endpoints; 2) new and refined methods to evaluate potential surrogate endpoints at both the individual patient and trial levels; and 3) implementation of novel phase II and III trial designs where multiple endpoints and/or predictive biomarkers exist. Specific Aim 1 will expand existing expertise in adaptive dose-finding designs by incorporating multivariate toxicity endpoints and using bivariate endpoints incorporating both toxicity and preliminary efficacy measures. In Specific Aim 2, novel methods for surrogate endpoint evaluation will be developed and rigorously tested using an already developed robust simulation engine. A novel design proposed by our group, the first to address the critical absence of implementation strategies for surrogate endpoints through a trial design making explicit and monitored use of a newly validated surrogate as its primary endpoint, will be enhanced in Specific Aim 3 to account for multiple putative surrogate endpoints or multiple biomarker-based subgroups with heterogeneous multi-endpoint performance within a new phase II or III trial. Each aim builds on existing expertise and strong preliminary data to advance the field in a novel yet practical manner that can be readily translated into clinical trial practice, taking advantage of the unique data and trial resources available at the Mayo Clinic. In particular, the research team at the Mayo Clinic under Dr. Sargent's leadership has the un-paralleled opportunity to directly translate these methodological advances in novel designs and endpoints into practice through implementation in upcoming oncology clinical trials.